Calhern was born in Brooklyn, New York, the son of Eugene Adolf Vogt and Hubertina Friese Vogt, both of whom were natives of Germany. He had one sibling, a sister. His father was a tobacco dealer. His family left New York while he was still a child and moved to St. Louis, Missouri, where he grew up. While Calhern was playing high school football, a stage manager from a touring theatrical stock company spotted him, and hired him as a bit player. (Another source says, "Grace George hired his St. Louis high school football team as supers for a Shakespearean play.")
Just prior to World War I, Calhern decided to move back to New York to pursue an acting career. He began as a prop boy and bit player with touring companies and burlesque companies. He became a matinee idol by virtue of a play titled Cobra
Calhern's Broadway credits include Roger Bloomer (1923), The Song and Dance Man (1923-1924), Cobra (1924), In a Garden (1925-1926), Hedda Gabler (1926), The Woman Disputed (1926-1927), Up the Line (1926), The Dark (1927), Savages Under the Skin (1927), A Distant Drum (1928), Gypsy (1929), The Love Duel (1929), The Rhapsody (1930), The Tyrant (1930), Give Me Yesterday (1931), Brief Moment (1931-1932), The Inside Story (1932), Birthday (1934-1935), Hell Freezes Over (1935-1936), Robin Landing (1937), Summer Night (1939), The Great Big Doorstep (1942), Jacobowsky and the Colonel (1944-1945), The Magnificent Yankee (1946), The Survivors (1948), The Play's the Thing (1948), King Lear (1950-1951), and The Wooden Dish (1955).
Calhern's burgeoning career was interrupted by the war, and he served overseas in the 143rd Field Artillery of the United States Army during World War I.
Calhern started working in silent films for director Lois Weber in the early 1920s; the most notable being The Blot in 1921. A 1921 newspaper article commented, "The new arrival in stardom is Louis Calhern, who, until Miss Weber engaged him to enact the leading male role in What's Worth While?, had been playing leads in the Morosco Stock company of Los Angeles."
In 1923 he left the movies, but would return to the screen eight years later after the advent of sound pictures. He was primarily cast as a character actor in films while he continued to play leading roles on the stage. He reached his peak in the 1950s as a Metro-Goldwyn-Mayer contract player. Among his most memorable screen roles were Ambassador Trentino in the Marx Brothers classic Duck Soup (1933) and three that he appeared in at MGM in 1950: a singing role as Buffalo Bill in the film version of the musical Annie Get Your Gun, the double-crossing lawyer and sugar-daddy to Marilyn Monroe in John Huston's film noir The Asphalt Jungle, and his Oscar-nominated performance as Oliver Wendell Holmes in The Magnificent Yankee (re-creating his role from the Broadway stage). He was also praised for his portrayal of the title role in the John Houseman production of Julius Caesar (adapted from the Shakespeare play) in 1953, directed by Joseph L. Mankiewicz. Calhern also played the role of the devious George Caswell, the manipulative board member of Tredway Corporation in the 1954 production of Executive Suite.
Calhern's other film roles included the grandfather in The Red Pony (1949), adapted from the novel by John Steinbeck and starring Robert Mitchum, and the spy boss of Cary Grant in the Alfred Hitchcock suspense classic Notorious (1946). A performance as Uncle Willie in High Society (1956), a musical remake of The Philadelphia Story, turned out to be his final film.
Calhern was married four times. First, to Ilka Chase (1900-1978) from 1926 to 1927, then to Julia Hoyt (1897-1955) from 1927 to 1932, and then to Natalie Schafer (1900-1991) from 1933 to 1942, and Marianne Stewart (1922-1992) from 1946 to 1955. All four marriages ended in divorce.
Calhern died of a sudden heart attack in Nara, Japan, while filming The Teahouse of the August Moon. He was replaced in the film by Paul Ford, who had played Calhern's role in the original stage version. By an odd coincidence, when playing Buffalo Bill in Annie Get Your Gun, Calhern had replaced Frank Morgan, who had died of a sudden heart attack during the making of that film. Calhern was cremated and is interred at Hollywood Forever Cemetery.Cobra (1921) as Jack Race
Gypsy (1929) as Cleve
The Magnificent Yankee (1946) as Justice Oliver Wendell Holmes, Jr.